Complement triggers relocation of Mortalin/GRP75 from mitochondria to the plasma membrane

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• 作者：Niv Mazkereth^a ; Francesco Rocca^b ; Jennifer-Rose Schubert^b ; Claudia Geisler^b ; Yaron Hillman^a ; Alexander Egner^b ; Zvi Fishelson^a ; ^{lifish@post.tau.ac.il" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AF488 ; Alexa Fluor 488 ; AU ; arbitrary units ; MAC ; complement membrane attack complex ; CDC ; complement-dependent cytotoxicity ; C5b-9 ; complement terminal complex composed of C5b ; C6 ; C7 ; C8 ; and C9 ; C9-AF546 ; human complement C9 tagged with Alexa Fluor 546 ; C9D ; C9-depleted ; NHS ; normal human serum ; HIS ; heat-inactivated human serum ; PFA ; paraformaldehyde ; PM ; plasma membrane ; STED ; Stimulated emission depletion
• 刊名：Immunobiology
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：221
• 期：12
• 页码：1395-1406
• 全文大小：3099 K

文摘

Mortalin/GRP75 is a ubiquitously expressed mitochondrial chaperon that is overexpressed in cancer. Mortalin protects cells from complement-dependent cytotoxicity (CDC) and facilitates elimination of the complement C5b-9 complexes from the cell surface. We performed a nanoscopical study aimed at imaging the distribution of the C5b-9 complexes in the plasma membrane and the postulated relocation of mortalin from the mitochondria to the plasma membrane. To gain a resolution of 35 nm, the locations of the C5b-9 complex and mortalin were imaged with a STED (Stimulated Emission Depletion) microscope at sub-diffraction resolution. Early changes in the spatial distribution of the C5b-9 on the cell surface are described. Juxtaposition of the labeled mortalin and C5b-9 at the plasma membrane region within minutes after complement attack is evident. Microscopical analysis of the distribution of mortalin in the vicinity of the mitochondria of complement-treated cells shows a more diffused pattern relative to control cells, proposing exit of mortalin from the mitochondria in response to complement-induced stress. In support, analysis of cytoplasmic mortalin by immunoblotting shows enhanced level of mortalin in the cytoplasm in complement-treated cells. Our data demonstrates that cells can sense complement activation at the plasma membrane and in response, swiftly send mortalin to this region in order to deactivate it.